The sequence-biological activities of the luteinizing hormone releasing hormone (LHRH) (Glp-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH.sub.2) and substance P (SP) (Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH.sub.2) differ in an important structural aspect. No truncated analog of LHRH is known which has activity equal to that of LHRH. Although LHRH is a decapeptide and SP is an undecapeptide, the removal of the N-terminal four or five amino acids of SP gives truncated hexa- and heptapeptides which show biological activities essentially equivalent ot that of SP itself. For example, the studies of Yanaihara et al. ["Substance P Nobel Symposium 37", U.S. von Euler and B. Pernow, eds., Raven Press, New York (1977) p. 27] exemplify data on sequence-activity of truncated analogs of SP, which showed that the hexapeptide, Glp-Phe-Phe-Gly-Leu-Met, and the heptapeptide, Glp-Gln-Phe-Phe-Gly-Leu-Met-NH.sub.2, showed 2.0 and 1.7 relative activities, respectively, in comparison with SP as 1.
It is generally believed in the field of SP that the N-terminal Arg.sup.1 -Pro.sup.2 -Lys.sup.3 -Pro.sup.4 - or Arg.sup.1 -Pro.sup.2 -Lys.sup.3 -Pro.sup.4 -Gln.sup.5 - of SP are not needed for biological activity and such statements imply the concept that these N-terminals four or five amino acids have no biological role whatsoever. This concept may not be entirely correct, because it is possible that these four or five N-terminal amino acids of SP have a role in binding at one or more receptors, particularly when one considers the strong functionality of Arg.sup.1 and Lys.sup.3 in these units. Also, the presence of Pro.sup.2 and Pro.sup.4 indicate a unique conformational contribution from the N-terminal portion of SP. Therefore, the presence of Arg.sup.1 -Pro.sup.2 -Lys.sup.3 -Pro.sup.4 - and Arg.sup.1 -Pro.sup.2 -Lys.sup.3 -Pro.sup.4 -Gln.sup.5 - should not be summarily dismissed from consideration of some nature of a biological role.
Doubtless, peptide chemists, in general, were attracted to synthesize truncated analogs of SP not only because the N-terminal moiety does not contribute to agonist mechanisms, but because truncated analogs can be more quickly synthesized, and at less expense, and probably be purified to a high state of purity more readily than the corresponding undecapeptides.
We have investigated truncated analogs of SP as antagonists in comparison with the corresponding undecapeptides. In doing so, we have surprisingly discovered certain undecapeptides which have higher antagonistic activity than any previously known analog of SP. We have also discovered that a certain truncated analog has substantially less antagonistic activity than that of the corresponding undecapeptide. This finding that a potent undecapeptide has substantially more antagonistic activity than a corresponding truncated peptide is not in agreement with the comparable agonistic activities of truncated analogs of substance P.